Post on 01-Aug-2020
Current Opinion in Pulmonary Medicine
MCP 2401
Precision medicine in Asthma: Linking phenotypes to targeted treatments
Kian Fan CHUNG MD DSc FRCP
National Heart & Lung Institute, Imperial College, London & Respiratory Biomedical Research Unit; Royal Brompton & Harefield NHS Trust and Imperial College London, United Kingdom.
Running title: Precision medicine for asthma
Correspondence:
Professor K F Chung,
National Heart & Lung Institute,
Imperial College London,
Dovehouse St,
London SW3 6LY, UK
Phone +44 207594 7959
f.chung@imperial.ac.uk
[1]
Abstract 196
Purpose of review:
Asthma is a heterogeneous disease consisting of different phenotypes that are driven by
different mechanistic pathways. The purpose of this review is to emphasise the important
role of precision medicine in asthma management.
Recent findings:
Despite asthma heterogeneity, the approach to management has been on the basis of
disease severity, with the most severe patients reserved for the maximum treatments with
corticosteroids and bronchodilators. At the severe end, the recent availability of biologic
therapies in the form of anti-IgE (omalizumab) and anti-IL5 therapies (mepolizumab and
reslizumab) has driven the adaptation of precision medicine. These therapies are reserved
for severe asthma with defined either allergic or eosinophilic background, respectively.
Summary:
Unbiased definition of phenotypes or endotypes (which are phenotypes defined by
mechanisms) is an important step towards the use of precision medicine in asthma. While
T2-high asthma has been defined with targets becoming available for treating allergic or
eosinophilic asthma, the definition of non-T2 phenotypes remains a priority. Precision
medicine is also dependent on the definition of biomarkers that can help differentiate
between these phenotypes and pinpoint patients suitable for specific-targeted therapies.
Thus, precision medicine links phenotypes (endotypes) to targeted treatments for better
outcomes.
Key words: Precision medicine, asthma, phenotyping, biomarkers.
[2]
Introduction
Asthma is diagnosed by the presence of intermittent symptoms of wheeze,
cough and chest tightness that usually resolves spontaneously or with asthma
treatments, and under such an umbrella term, would exist different phenotypes of
asthma. In fact, the Global Initiative for Asthma (GINA) has now recognised asthma
as being a heterogeneous disease with different presentations, outcomes and
underlying mechanisms. Clinicians have defined several phenotypes based on the
presentation and age of onset of symptoms, the severity of the disease, and the
presence of other conditions such as allergy and eosinophilia. When these
phenotypes have been linked to long-term outcomes or to response to therapy with
corticosteroids, these have been used by clinicians to predict the course of asthma.
Despite the recognition of these phenotypes of asthma, the approach to the
management of asthma continues to be based on the severity of the condition, with
drugs added on the basis of asthma control.
Inhaled corticosteroid (ICS) therapy remains the cornerstone of treatment of
asthma because asthma is recognised as an eosinophilic inflammatory condition;
however, those who respond to ICS therapy with an improvement in lung function
such as the forced expiratory volume measured in one second (FEV1) are associated
with eosinophilia, and these usually represent up 50% of asthmatics (1, 2). Use of
blood eosinophil count as a biomarker to define responders to ICS is not used.
Treatment of patients with asthma based on their sputum eosinophil counts rather
than on symptoms results in better control of asthma with less exacerbations using
less corticosteroid therapy (3). There may be many reasons why this approach of
using sputum eosinophil counts to improve the therapy of asthma has not been
adopted. Most importantly, obtaining sputum samples from patients with asthma is
[3]
not always successful and the analysis of the samples takes time and effort. Thus,
the practice of precision (or personalised) medicine in asthma is lagging behind.
However, the introduction of specific biologic therapies such as anti-IgE and anti-IL5
antibody treatments at the Step 5 of the GINA guidelines has opened up the new era
of precision medicine in asthma. These therapies are only used in the severe allergic
asthma and in the severe eosinophilic phenotypes of asthma, respectively.
Although the practice of medicine has always been based on a personalised
approach since the dawn of medicine, with the concept of treating each patient as
being unique, this delivery has remained very limited mainly as a concept rather than
hard practice because of limitations in our understanding of what constitutes asthma.
Currently, we recognise a category of asthma as being ‘severe asthma’, defined as
by poor therapeutic responses of these patients to currently-approved asthma
medications, particularly inhaled and oral CS therapies, and approaches to
phenotyping have been proposed in the international severe asthma guidelines (4).
The clinical diversity of this group has been recognised and this group of patients
has been the subject of unbiased clustering approaches.
Phenotypes of asthma have not been well described and there has been a
lack of biomarkers developed for identifying different types of asthma. Consequently,
the treatment of asthma has remained a ‘one size fits all’. Treatments should not
only be based on the basis of severity, but on the basis of the driving mechanisms.
The introduction of new biologic therapies at Step 5 has heralded a new era of
precision medicine for asthma. This review will discuss how precision medicine will
alter the approach to the management of asthma.
What is Precision Medicine?
[4]
Precision medicine can be defined as an approach to treat and prevent
disease by taking into consideration the individual variability in genes, environment,
and lifestyle for each subject and by taking this approach, there is increased
likelihood of treating ‘the right patient with the right drug at the right time’, with
preventive measures and therapies tailored for each individual (5). Analysis of the
genes and proteins are more likely to point towards causative pathways, that would
lead to definition of endotypes which are phenotypes defined according to
mechanisms. This is more likely to lead to treatments that target the cause of these
diseases. Precision medicine is the tailoring of medical management to the individual
characteristics not only genetic or genomic but also environmental and psychosocial
characteristics, and preferences of each patient. Other terms that are used often
synonymously with precision medicine are tailored medicine, stratified medicine or
targeted medicine that will ultimately lead to targeted therapeutics. The concept of
the “P4 medicine” that is predictive, preventive, personalized, and participatory also
falls within a similar definition (https://www.systemsbiology.org/research/p4-
medicine/).
In order to be able to practise precision medicine with particular reference to
asthma, one should understand the different endotypes of asthma and the
biomarkers that will be used to help the doctor in determining the right treatment. In
addition, because asthma is a disease that changes with time, information on a daily
basis about the patient’s condition and environment that could influence the course
of the disease is needed. Such daily information may be used to predict any future
exacerbations of asthma and the influence of potential environmental factors.
Phenotyping to endotyping
[5]
Description of clinical phenotypes based on clinical variables and
inflammatory markers has been made possible by the use of unbiased methods of
clustering. The most recent report from the U-BIOPRED cohort described a well-
controlled moderate-to-severe asthma phenotype and 3 other severe phenotypes: (i)
late-onset asthma with past or current smoking and chronic airflow obstruction,
predominantly eosinophilic inflammation (ii) non-smoking severe asthma with chronic
airflow obstruction and high use of oral corticosteroid therapy and (iii) obese female
patients with frequent exacerbations but with normal lung function (6) (Fig 1). In the
American Severe Asthma Research Project (SARP) cohort, phenotypes of early
onset atopic asthma with mild to moderate severity, of obese late onset non-atopic
asthma female patients with frequent exacerbations, and of those with severe airflow
obstruction with use of oral corticosteroid therapy were identified (7). In the Leicester
cohorts, the use of sputum eosinophilia as a marker of eosinophilic asthma (8), has
resulted in the description of 2 cohorts: a cluster of non-eosinophilic inflammation
(early-onset, symptom-predominant group in female obese patients), and a cluster of
eosinophilic inflammation with late-onset disease, associated with rhinosinusitis,
aspirin sensitivity, and recurrent exacerbations. This latter eosinophilic phenotype
was also described in the SARP cohort with late onset asthma and nasal polyps with
exacerbations despite high systemic corticosteroid use; the other eosinophilic cohort
had early onset allergic asthma with low lung function (9). This clustering based on
clinical, physiological and inflammatory parameters while yielding distinct
phenotypes have not in general led to the elaboration of phenotypic biomarkers.
Definition of a severe eosinophilic asthma phenotype/endotype
[6]
Molecular phenotyping has allowed us to define the severe eosinophilic
asthma phenotype as an endotype, ie a phenotype defined by underlying
mechanisms. The clinical phenotype characterized by concomitant high blood and
sputum eosinophilia has been associated with very poor asthma control and
propensity to asthma exacerbation (9). The unbiased cluster analyses have
uncovered a phenotype of patients with late-onset, eosinophilic inflammation-
predominant asthma (6-8), and adult-onset asthma patients with a high blood
eosinophil count with frequent exacerbations and a poor prognosis (10). Persistent
airflow limitation and distal inflammation with air trapping are common in these
patients, as is upper airway pathology such as chronic rhinosinusitis with nasal
polyposis (11). Molecular support for this endotype was provided by determining the
expression of 3 genes upregulated by exposing airway epithelial cells to the T2
cytokine, IL-13, in airway epithelial cells of patients with asthma. A Th2-high
molecular phenotype was characterised by more blood and BAL eosinophils,
increased levels of serum IgE, increased expression of mucin MUC5AC, increased
expression of IL5 and IL13 in biopsies, increased bronchial hyperresponsiveness,
and respond to inhaled corticosteroids by an increase in FEV1 when compared to
those with Th2-low expression (12). Finally, the recent sputum analysis of U-
BIOPRED has defined the molecular shape of this endotype associated with high T2
pathway and also with mast cell activation pathway (13). New targeted treatments
such as anti-IL5 and anti-IL5ra antibody that caused a reduction in the exacerbation
rate support the concept that this is a severe eosinophilic asthma endotype (14, 15).
The major criteria for this endotype have been defined as (1) having severe asthma,
(2) with high load eosinophilic disease, (3) having frequent exacerbations, and (4)
the need for oral corticosteroid therapy to maintain control (16).
[7]
Unbiased molecular phenotyping
The Th2-high phenotype is only found in 37% of patients with severe asthma
when analysing genes in the airway epithelium (17). Therefore, the majority of
patients with severe asthma can be considered to be low-T2. In order to elucidate
these non-T2 endotypes, an unbiased approach to obtaining molecular phenotypes
of asthma was undertaken in U-BIOPRED. A hierarchical clustering of differentially-
expressed genes between eosinophilic and non-eosinophilic inflammatory profiles
from an analysis of sputum omics data revealed 3 molecular phenotypes (13). One
cluster was characterised by the immune receptors IL33R, CCR3 and TSLPR with
the highest enrichment of gene signatures for interleukin-13/T-helper cell type 2
(Th2) and innate lymphoid cell type 2 associated with the highest sputum
eosinophilia: this grouped patients with severe asthma with oral corticosteroid
dependency, frequent exacerbations and severe airflow obstruction. The second
cluster was characterised by interferon-, tumour necrosis factor-α- and
inflammasome-associated genes with the highest sputum neutrophilia, serum C-
reactive protein levels and prevalence of eczema. The third phenotype was
characterised by genes of metabolic pathways, ubiquitination and mitochondrial
function with paucigranulocytic inflammation and little airflow obstruction (13). The
second phenotype is in agreement with the report that in neutrophilic asthma, an
elevated gene expression of NLRP3, caspase-1 and IL-1β was seen in sputum
macrophages (18). Thus, this unbiased approach has provided an overall idea of the
various pathways associated with these 3 phenotypes of asthma, with the possibility
that each of these phenotypes is underlined by several interacting pathways.
[8]
Therefore, within this categorisation, it has been possible to define an
eosinophilic inflammation phenotype, a neutrophilic phenotype and a
paucigranulocytic phenotype according to sputum cell measurements. Furthermore,
each inflammatory phenotype was observed with several pathways that could
contribute to the definition of the phenotype. However, because there has been no
validation of these pathways yet, it is not possible to describe these as endotypes
yet. One could consider the cluster associated with the highest expression of T2 and
ILC2 pathway signature and sputum eosinophilia to be a severe eosinophilic asthma
endotype. On the other hand, the neutrophilic cluster associated with inflammasome
activation cannot be considered an endotype yet, because the role of the
inflammasome in this cluster is yet to be defined. Nevertheless, this remains a
potential therapeutic target for this cluster. Similarly, this similar argument can be
made for the third cluster that may be driven by mitochondrial oxidative stress
pathways.
Development of targeted therapies
Recent progress in the therapy of severe asthma has been marked by the
introduction of biologic treatments as add-on treatment to Step 5 of the GINA
guidelines. Such biologic treatments have now been important in defining the target
population, not only because these treatments are relatively expensive compared to
existing ones but also because such specific targeting need to be used only in those
who have the target abnormality. However, cost-effectiveness analyses will be
needed to determine the true costs of these treatments. These biologic treatments
being very specific in their actions in targeting single cytokines have opened up the
field of precision medicine, placing the emphasis on the application of precision
[9]
medicine in severe asthma since the correct patient need to be singled out for these
specifically-targeted treatments. The greatest emphasis has been on the targeted
treatments for the T2 pathway, while treatments targeted at non-T2 pathways have
been less successful (19).
Targeting the T2 pathway
Activation of Th2 and ILC2 cells can occur through the release of innate
cytokines, such as thymic stromal lymphopoietin (TSLP), interleukin IL-25, and
interleukin 33 from the epithelium, that can be induced by external stimuli such as
lipopolysaccharide, pollutants, and viruses (20). These activated Th2 or ILC2 cells
release interleukins 4, 5, and 13IL4, 5 and 13, which are expressed in the bronchial
submucosa of patients with asthma. The new biologic treatments available for
patients with severe asthma include anti-IgE antibody and anti-IL5 antibody.
Anti-IgE antibody prevents the binding of free IgE to IgE receptors on mast
cells and basophils by binding itself to free IgE. IgE production from B cells is under
the control of the T2 cytokines, IL-4 and IL-13. Anti-IL5 antibody is targeted towards
IL-5, produced by Th2 cells and ILC2s, and is important for the terminal
differentiation and maturation of eosinophils in the bone marrow and for the
mobilisation of eosinophils and eosinophil precursors into the circulation. Both anti-
IgE antibody and anti-IL5 antibody are targeted for use in patients with severe
asthma, the former for allergic asthmatics and the latter for eosinophilic asthma. In
severe persistent allergic asthma defined by patients with an allergic background
with raised serum IgE levels and at Step 4 or 5 of GINA guidelines, omalizumab, an
anti-IgE antibody, as an add-on therapy decreased severe asthma exacerbations by
26%, compared with placebo (21). Mepolizumab and reslizumab, anti-IL5 antibodies,
[10]
have been shown to benefit allergic and eosinophilic severe asthma respectively by
reducing asthma exacerbation frequency and also improving baseline airflow
obstruction (22, 23): the patients chosen for these studies had to show a raised level
of blood eosinophil count. Other potential therapies not yet approved targeting T-2
pathway include anti-IL5Rα antibody (benralizumab) that inhibits the effect of IL5 (24,
25), and anti-IL4Rα antibody (dupilumab) (26), that blocks the effects of IL-13 and IL-
4 together, both showing beneficial effects on exacerbations and lung function,
particularly in those with a raised blood eosinophil count.
More recently, tezepelumab (AMG 157/MEDI9929), a human monoclonal
antibody specific for the epithelial-cell-derived cytokine TSLP which regulates type 2
immunity through not only Th2 cells but also through ILC2 cells, has been associated
with lower rates of clinically significant asthma exacerbations than those who
received placebo, independent of baseline blood eosinophil counts to in patients with
uncontrolled moderate-to-severe asthma (27).
Non-T2 targets
There have been descriptions of non-T2 phenotypes previously. Thus, a
systemic IL-6 inflammation with clinical features of metabolic dysfunction associated
with more severe asthma has been described (28). In addition, apart from Th2 high,
a Th17 high group has been described with the Th2 high being mutually exclusive of
Th17 high (29). However, despite this targeting non-T2 targets has not proven to be
successful in providing effective therapies for asthma. Brodalumab, a human anti-
interleukin-17RA monoclonal antibody, had no effect on asthma control scores,
symptom-free days, and FEV1 in patients with inadequately controlled moderate-to-
severe asthma who were receiving inhaled corticosteroid therapy (30). Treatment
[11]
with a selective CXCR2 antagonist, AZD5069, that blocks the effect of CXCL8, did
not reduce the frequency of severe exacerbations in patients with uncontrolled
severe asthma (31). Finally, in adults with uncontrolled severe persistent asthma, the
anti-TNFα antibody golimumab had no overall beneficial effects (32). These have
raised the issue as to whether a neutrophilic asthma phenotype does exist (33), but it
is more likely that the reason for the failure of these therapies is that the right
patients were not chosen for these therapies with the lack of the appropriate
biomarkers.
The molecular phenotypes derived from sputum transcriptomic analysis in U-
BIOPRED defined a neutrophilic inflammatory phenotype (sputum neutrophil >73%),
with inflammasome, IFN and TNF activation pathways (13). This could be associated
with the microbial dysbiosis that is now increasingly being associated with severe
asthma (34), but further validation research is needed to definitely determine the
mechanism underlying the neutrophilic inflammation. Analysis of transcriptomics in
bronchial biopsies and brushings identified the co-expression of high Th2 and high
Th1 pathways indicating that more than one pathway may co-exist (35). A raised
concentration of the gastrotransmitter, hydrogen sulphide, in sputum has also been
associated as a potential biomarker of neutrophilic asthma associated with airflow
obstruction (36).
Biomarkers for precision medicine
In order to define the phenotypes that constitute the whole range of asthma
and to find the patients who will respond to specific therapies, it is important to define
the biomarkers that will help the clinician to select the right therapy for the right
patient. A biomarker can be defined as a characteristic that can be measured and
[12]
evaluated as an indicator of normal or pathological biological processes or the
biological response to a therapeutic intervention (37). Biomarkers mostly indicative of
T2-high asthma that are easily accessible to the patient are available for the
management of asthma; these include blood eosinophil count and serum IgE and
also serum periostin levels, levels of nitric oxide in exhaled breath (FeNO) and
sputum eosinophil count in some centres. Using sputum eosinophil counts as a
response biomarker to treatment with corticosteroid therapy results in better outcome
measures mainly in terms of a reduction in exacerbations compared to using
symptom severity (38). FeNO did not perform as well. Responsiveness to
corticosteroid therapy particularly in children can be predicted from a blood
eosinophil count (39), but validated cut-off levels in different populations still need to
be established. Increasingly, biomarkers will be used to select patients that would
be suitable for specific biological treatments. Baseline blood eosinophil count is
being used as a biomarker that predicts the clinical efficacy of anti-IL5 therapy in
patients with severe eosinophilic asthma with a history of exacerbations (15, 22, 40,
41) . Total serum IgE level has been used as a response biomarker for the use of
anti-IgE antibody, omalizumab, in the treatment of severe allergic asthma. High
levels of FeNO (>19.5 parts per billion) and blood eosinophil count (>260/μl)
significantly predicted those responding to omalizumab with a reduction in
exacerbations (42).
There is an increasing need for developing biomarkers that will guide
clinicians in the management of asthma. The following areas need further
development: (i) definition of molecular phenotypes of asthma, particularly those in
the non-T2/Th2 pathways (ii) develop more phenotypic and predictive biomarkers to
delineate these molecular phenotypes of asthma and (iii) obtain specific biomarkers
[13]
to predict therapeutic outcomes to more specific targeted therapies. An unbiased
approach is necessary to define the phenotypes of asthma.
While the use of omics data from multiple platforms including transcriptomics,
proteomics, lipidomics or metabolonomics in lung tissue compartments holds the
best chance of obtaining endotypes (43, 44), biomarkers need to be developed in
easily-accessible compartments, so-called bedside biomarkers, that can be assayed
relatively easily. Thus, assays involving exhaled breath, blood or urine would appear
more promising. Therefore, one unmet need is how to develop such bed-side
biomarkers. The other possibility is that composite biomarkers may be another
answer to this (45).
Conclusion
Because of the heterogeneity and complexity of asthma, a different approach from
current practice is needed to the management of asthma that takes into account
these varied features of the disease. The use of omics data and unbiased clustering
together with the use of clinical features, physiological and inflammatory data will
provide greater opportunity of phenotyping asthma according to the mechanisms
driving the disease thus leading to endotype definition. Biomarkers could be used to
define and categorise these endotypes. This will be a tremendous help for the
development of precision medicine for asthma that will allow for more precise
treatment aims and also provide a source of novel targets and hence new treatments
for each defined endotype. Precision medicine should be applied to the whole
spectrum of asthma, not just at the more severe end of the disease.
[14]
Key points
1. Severe asthma is a heterogeneous condition and phenotyping of patients with
severe asthma into a T2 and non-T2 category is possible.
2. Precision medicine is being introduced with the availability of biologic
therapies targeting IgE and IL-5, because these agents are targeted towards
specific phenotypes of severe asthma.
3. The future of precision medicine in asthma will depend on the unbiased
recognition of all the molecular phenotypes or endotypes of asthma, and the
definition of associated biomarkers.
Acknowledgements:
KFC is a Senior Fellow of the National Institute for Health Research, UK. He also
acknowledges support from the Medical Research Council and European Union.
Financial disclosure
KFC reports personal fees from Advisory Board membership with GSK, Boehringer
Ingelheim, Novartis, Astra-Zeneca and Teva, personal fees from payments for
lectures from Astra-Zeneca, Novartis and Merck, and grants for research to his
institution from Merck and GSK, all in relation to asthma, COPD and cough.
[15]
Legend to Fig:
Fig 1. Clinical phenotypes of moderate-severe asthma derived from U-BIOPRED cohort from a cluster analysis of 8 clinico-physiologic parameters. Reproduced from Reference 6 (with permission).
[16]
References
1. Green RH, Brightling CE, Woltmann G, Parker D, Wardlaw AJ, Pavord ID. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax. 2002;57(10):875-9.2. Schleich FN, Manise M, Sele J, Henket M, Seidel L, Louis R. Distribution of sputum cellular phenotype in a large asthma cohort: predicting factors for eosinophilic vs neutrophilic inflammation. BMC pulmonary medicine. 2013;13:11.3. Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet. 2002;360(9347):1715-21.4. Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343-73.5. Chung KF. New treatments for severe treatment-resistant asthma: targeting the right patient. The lancet Respiratory medicine. 2013;1(8):639-52.6. Lefaudeux D, De Meulder B, Loza MJ, Peffer N, Rowe A, Baribaud F, et al. U-BIOPRED clinical adult asthma clusters linked to a subset of sputum -omics. J Allergy Clin Immunol. 2016; 139: 1797-1807.7. Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med. 2010;181(4):315-23.8. Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M, Brightling CE, et al. Cluster analysis and clinical asthma phenotypes. AmJRespir Crit Care Med. 2008;178(3):218-24.9. Wu W, Bleecker E, Moore W, Busse WW, Castro M, Chung KF, et al. Unsupervised phenotyping of Severe Asthma Research Program participants using expanded lung data. J Allergy Clin Immunol. 2014;133(5):1280-8.10. Price DB, Rigazio A, Campbell JD, Bleecker ER, Corrigan CJ, Thomas M, et al. Blood eosinophil count and prospective annual asthma disease burden: a UK cohort study. The lancet Respiratory medicine. 2015;3(11):849-58.11. de Groot JC, Storm H, Amelink M, de Nijs SB, Eichhorn E, Reitsma BH, et al. Clinical profile of patients with adult-onset eosinophilic asthma. ERJ Open Res. 2016;2(2).12. Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, Ellwanger A, et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. AmJRespir Crit Care Med. 2009;180(5):388-95.13. Kuo CS, Pavlidis S, Loza M, Baribaud F, Rowe A, Pandis I, et al. T-helper cell type 2 (Th2) and non-Th2 molecular phenotypes of asthma using sputum transcriptomics in U-BIOPRED. Eur Respir J. 2017;49(2).14. Chupp GL, Bradford ES, Albers FC, Bratton DJ, Wang-Jairaj J, Nelsen LM, et al. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. The lancet Respiratory medicine. 2017; 5: 390-400.15. Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting beta2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016; 388:2115-2127.16. Buhl R, Humbert M, Bjermer L, Chanez P, Heaney LG, Pavord I, et al. Severe eosinophilic asthma: a roadmap to consensus. Eur Respir J. 2017;49(5).17. Pavlidis S. LM, Baribaud F., Kuo C-H., Rowe A., Lutter R. ,Hoda U., Rossios C., Sousa A., Corfield J., Adcock I., Djukanovic R. , Sterk P., Chung K.F. Th2 subsetting of U-BIOPRED asthma subjects based on airway transciptomic profiles. Eur Respir J. 2015; 46(Suoppl 59):OA1772; DOI: 10.183/13993003.congress-2015.
[17]
18. Simpson JL, Phipps S, Baines KJ, Oreo KM, Gunawardhana L, Gibson PG. Elevated expression of the NLRP3 inflammasome in neutrophilic asthma. Eur Respir J. 2014;43(4):1067-76.19. Chung KF. Targeting the interleukin pathway in the treatment of asthma. Lancet. 2015;386(9998):1086-96.20. Licona-Limon P, Kim LK, Palm NW, Flavell RA. TH2, allergy and group 2 innate lymphoid cells. Nature immunology. 2013;14(6):536-42.21. Humbert M, Beasley R, Ayres J, Slavin R, Hebert J, Bousquet J, et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy. 2005;60(3):309-16.22. Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371(13):1198-207.23. Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. The lancet Respiratory medicine. 2015;3(5):355-66.24. Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting beta2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2115-27.25. FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, et al. Benralizumab, an anti-interleukin-5 receptor alpha monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2128-41.26. Wenzel S, Castro M, Corren J, Maspero J, Wang L, Zhang B, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting beta2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet. 2016;388(10039):31-44.27. Corren J, Parnes JR, Wang L, Mo M, Roseti SL, Griffiths JM, et al. Tezepelumab in Adults with Uncontrolled Asthma. N Engl J Med. 2017;377(10):936-46.28. Peters MC, McGrath KW, Hawkins GA, Hastie AT, Levy BD, Israel E, et al. Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts. The lancet Respiratory medicine. 2016;4(7):574-84.29. Choy DF, Hart KM, Borthwick LA, Shikotra A, Nagarkar DR, Siddiqui S, et al. TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma. Science translational medicine. 2015;7(301):301ra129.30. Busse WW, Holgate S, Kerwin E, Chon Y, Feng J, Lin J, et al. Randomized, Double-Blind, Placebo-controlled Study of Brodalumab, a Human Anti-IL-17 Receptor Monoclonal Antibody, in Moderate to Severe Asthma. Am J Respir Crit Care Med. 2013;188(11):1294-302.31. O'Byrne PM, Metev H, Puu M, Richter K, Keen C, Uddin M, et al. Efficacy and safety of a CXCR2 antagonist, AZD5069, in patients with uncontrolled persistent asthma: a randomised, double-blind, placebo-controlled trial. The lancet Respiratory medicine. 2016;4(10):797-806.32. Wenzel SE, Barnes PJ, Bleecker ER, Bousquet J, Busse W, Dahlen SE, et al. A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma. AmJ Respir Crit Care Med. 2009;179(7):549-58.33. Chung KF. Neutrophilic asthma: a distinct target for treatment? The lancet Respiratory medicine. 2016;4(10):765-7.34. Chung KF. Airway microbial dysbiosis in asthmatic patients: A target for prevention and treatment? J Allergy Clin Immunol. 2017;139(4):1071-81.35. Kuo CS, Pavlidis S, Loza M, Baribaud F, Rowe A, Pandis I, et al. A Transcriptome-driven Analysis of Epithelial Brushings and Bronchial Biopsies to Define Asthma Phenotypes in U-BIOPRED. Am J Respir Crit Care Med. 2017;195(4):443-55.
[18]
36. Saito J, Zhang Q, Hui C, Macedo P, Gibeon D, Menzies-Gow A, et al. Sputum hydrogen sulfide as a novel biomarker of obstructive neutrophilic asthma. J Allergy Clin Immunol. 2013;131(1):232-4.37. Amur S, LaVange L, Zineh I, Buckman-Garner S, Woodcock J. Biomarker Qualification: Toward a Multiple Stakeholder Framework for Biomarker Development, Regulatory Acceptance, and Utilization. Clin Pharmacol Ther. 2015;98(1):34-46.38. Petsky HL, Cates CJ, Lasserson TJ, Li AM, Turner C, Kynaston JA, et al. A systematic review and meta-analysis: tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils). Thorax. 2012;67(3):199-208.39. Gaillard EA, McNamara PS, Murray CS, Pavord ID, Shields MD. Blood eosinophils as a marker of likely corticosteroid response in children with preschool wheeze: time for an eosinophil guided clinical trial? Clin Exp Allergy. 2015;45(9):1384-95.40. Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012;380(9842):651-9.41. Ortega HG, Yancey SW, Mayer B, Gunsoy NB, Keene ON, Bleecker ER, et al. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. The lancet Respiratory medicine. 2016;4(7):549-56.42. Hanania NA, Wenzel S, Rosen K, Hsieh HJ, Mosesova S, Choy DF, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. AmJRespirCrit Care Med. 2013;187(8):804-11.43. Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet. 2008;372(9643):1107-19.44. Chung KF, Adcock IM. Clinical phenotypes of asthma should link up with disease mechanisms. Current opinion in allergy and clinical immunology. 2015;15(1):56-62.45. Heaney LG, Djukanovic R, Woodcock A, Walker S, Matthews JG, Pavord ID, et al. Research in progress: Medical Research Council United Kingdom Refractory Asthma Stratification Programme (RASP-UK). Thorax. 2015; 71: 187-9.
[19]